Nozzles for nasal drug delivery

ABSTRACT

A nozzle for use in delivering a mixture of aerosol propellant and drug formulation. The nozzle includes a drug product inlet configured to receive a mixture of aerosolized propellant and an intranasal dosage form. The inlet is disposed at the proximal end. A nozzle body is secured to the drug product inlet. Two or more channels are disposed within the body. Two or more orifice apertures are disposed at the distal end of the nozzle.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application which claims priority of aU.S. patent application Ser. No. 14/075,126, filed Nov. 8, 2013,entitled, “Nozzles for Nasal Drug Delivery,” which claims priority froman international patent application PCT/US12/37132, filed May 9, 2012,entitled “Nozzles for Nasal Drug Delivery, which claims priority fromU.S. Provisional Application Ser. No. 61/484,048, filed May 9, 2011,entitled “Nozzles for Nasal Drug Delivery,” which applications arehereby incorporated by reference herein in their entirety.

STATEMENT CONCERNING GOVERNMENT INTEREST

The instant invention was made with U.S. government funding pursuant toUS Army SBIR grant W81XWH-10-C-0238. The Government may have certainrights in this application.

BACKGROUND

Existing nasal drug delivery devices do a poor job of penetrating thenasal cavity to deposit drug onto the medial turbinates for systemicdelivery. Such existing devices are also lacking in delivering drug tothe upper nasal cavity for direct nose-to-brain delivery. Existing nasaldrug delivery devices generate a wide plume which inadequately deliversa compound deep into the nasal cavity.

SUMMARY

In one embodiment, a nozzle is described and claimed including a drugproduct inlet configured to receive a mixture of aerosolized propellantand an intranasal dosage form, the inlet disposed at the proximal end, anozzle body defining two or more channels, the channels having aproximal and distal end, the body defining a longitudinal axis, and, anorifice disposed at the distal end of each channel.

In an aspect, the channels are disposed parallel to the longitudinalaxis.

In another aspect, the channels are disposed at an angle with respect tothe longitudinal axis.

In an aspect, the nozzle includes from five to seven channels.

In an aspect, the channels are circular and tubular in shape.

In an aspect, the channels are conical in shape.

In an aspect, four circular orifice apertures configured in a squareorientation are disposed at the distal end of the nozzle.

In an aspect, five circular orifice configured in a pentagonalorientation are disposed at the distal end of the nozzle.

In an aspect, six circular orifice configured in a hexagonalconfiguration are disposed at the distal end of the nozzle.

In an aspect, six circular orifice configured in a centered pentagonalconfiguration are disposed at the distal end of the nozzle.

In an aspect, four circular orifice configured linearly are disposed atthe distal end of the nozzle.

In an aspect, four rectangular orifice configured radially are disposedat the distal end of the nozzle.

In an aspect, five star-shaped orifice configured in a pentagonalconfiguration are disposed at the distal end of the nozzle.

In an aspect, the channels are plastic or metal tubes, the body is aplastic or metal tube, and, voids are disposed between the channels andbody.

In another embodiment, a nozzle for delivering a compound to an upperolfactory region of a user is disclosed including a nozzle body having acentral axis, a plurality of channels housed within the nozzle body, thechannels having a proximal end and a distal end, an inlet disposed atthe proximal end of the channel, an outlet orifice disposed at thedistal end of the channel, the outlet orifice arranged parallel to thecentral axis of the nozzle.

In an aspect, a line drawn thru a point on the outlet orifice is anequal distance to the central axis of the nozzle.

In an aspect, the outlet orifices are arranged so that a narrow plumeexits the nozzle.

In an aspect, the angle of the plume is about 5 degrees, about 4degrees, about 3 degrees, about 2 degrees, about 1 degree.

In yet another aspect, the angle of the plume is about 5 degrees.

In an aspect, the impact force delivered by the nozzle is decreased.

In an aspect, the delivery time for the compound is decreased.

In another embodiment, a nozzle for delivering a compound to an upperolfactory region of a user is disclosed including a nozzle body, acompound channel housed within the nozzle body, the compound channelhaving a proximal end and a distal end, the proximal end capable ofreceiving a compound, the distal end of the compound channel having anoutlet orifice, and a propellant channel, the propellant channel havinga proximal end and a distal end, the proximal end capable of receiving apropellant, the distal end of the propellant channel having an outletorifice, the compound channel being centered within the propellantchannel wherein the compound and the propellant are capable of beingemitted from the from outlet orifice.

In an aspect, the nozzle includes at least a second compound channel,wherein the nozzle is capable of delivering more than one compound at atime.

In another aspect, the compound delivered by the nozzle is a liquid, apowder, a gas, or combinations thereof.

In another aspect, the nozzle further includes a check shut off valvewherein the check shut off valve prevents propellant from flowingthrough the compound chamber once the compound is released.

DESCRIPTION OF DRAWINGS

FIG. 1 shows cross-sectional side view and distal view of a nozzleembodiment.

FIG. 2 shows a cross-sectional side view of another nozzle embodiment.

FIG. 3 shows a cross-sectional side view of another nozzle embodiment.

FIG. 4 shows a cross-sectional side view of another nozzle embodiment.

FIG. 5 shows a cross-sectional side view of another nozzle embodiment.

FIG. 6 shows a cross-sectional distal view of another nozzle embodiment.

FIG. 7 shows a cross-sectional distal view of another nozzle embodiment.

FIG. 8 shows a cross-sectional distal view of another nozzle embodiment.

FIG. 9 shows a cross-sectional distal view of another nozzle embodiment.

FIG. 10 shows a cross-sectional distal view of another nozzleembodiment.

FIG. 11 shows a cross-sectional distal view of another nozzleembodiment.

FIG. 12 shows a cross-sectional distal view of another nozzleembodiment.

FIG. 13 shows a cross-sectional side view of another nozzle embodiment.

FIG. 14 shows a cross-sectional side view of another nozzle embodiment.

FIG. 15 is a graph of percent deposition versus vertical spray angle forvarious nozzle and outlet orifice embodiments set forth in the Examplesand Figures herein. In this graph the zero angle is defined as theoptimal angle from the naris to the olfactory region.

FIG. 16 is a graph of percent deposition versus horizontal spray anglefor various nozzle and outlet orifice embodiments set forth in theExamples and Figures herein. In this graph the zero angle is defined asthe optimal angle from the naris to the olfactory region.

FIG. 17 is a photograph of the side and distal end of nozzle 18.

FIG. 18 is a photograph of the side and distal end of nozzle 35B.

FIG. 19 is a photograph of the side and distal end of nozzle 31.

FIG. 20 is a photograph of the side and distal end of nozzle 33.

FIG. 21 is a photograph of the side and distal end of nozzle 17.

FIG. 22 shows nozzle number 3.

FIG. 23 shows nozzle number 4.

FIG. 24 shows nozzle number 7.

FIG. 25 shows nozzle number 8.

FIG. 26 shows nozzle number 9.

FIG. 27 shows nozzles A, B, and C of Example 11.

FIG. 28 shows nozzle D of Example 11.

FIG. 29 shows a spray deposition (Method 3) comparison of 4 nozzles, twosingle channel nozzles and two 5 channel nozzles. Nozzle performance wastested over an extended distance range. To minimize the blotter wickingartifact, dose size was reduced to 10 microliters.

FIG. 30 shows frame captured images from high speed video of powderdosing. Comparison of plume geometry for three powder nozzles.

FIG. 31 shows frame capture from high speed video of powder plumes for azero bypass nozzle (simple tube) and a high bypass nozzle. These shotswere carried out between two plastic plates with a spacing of 1.8 mm,dimensions comparable to that found in the nasal sinus. Two times duringthe development of the plume after actuation initiation are shown. Theperformances with two different propellants are also compared.

DETAILED DESCRIPTION

Described herein are nozzles that deliver a compound into the posteriorregions of the nasal cavity. Current nasal delivery systems do notadequately deposit drug in posterior regions of the nasal cavity such asthe respiratory epithelium and olfactory region. Described herein arenozzles that enhance drug deposition into these regions of the nasalcavity.

The nozzles disclosed herein consistently deposit at least a majorityfraction of dose into the distal parts of the nasal cavity such as therespiratory epithelium and olfactory region. A drug product (alsoreferred to as drug formulation, intranasal dosage form and other liketerms used in the art) is propelled with a velocity via the nozzle intothe nasal cavity.

The nozzle may be used to deliver a compound to the upper olfactoryregion of a mammal or other animal. For instance, the user may be ahuman or non-human primate. The nozzle may have adult or pediatricusers. In some aspects, the nozzle may be used in veterinary medicine.In some aspects, the nozzle may be used to deliver a therapeutic orpalliative care compound.

Like named structures in the various embodiments function in the similaror same manner, are structurally the same or similar, and may be used infor the same or similar purpose.

A nozzle is disclosed with a plurality of outlet orifices for deliveryof a compound. The nozzle has a central longitudinal axis. The nozzlehouses a plurality of channels. The channels have a proximal end atwhich the compound to be delivered enters the channel and a distal endat which the compound exits the channel via an outlet orifice. Incertain embodiments, the channels run parallel to the central axis ofthe nozzle. In other embodiments, the channels run substantiallyparallel to the central axis of the nozzle in that a line drawn thru apoint on the outlet orifice is of equal distance to the central axis ofthe nozzle.

The outlet orifices are arranged in parallel alignment with the centralaxis of the nozzle. In one aspect, the outlet orifices are arrangedwhere a line drawn through the orifice has an equal distance from a linedrawn through the center of the nozzle. In yet another aspect, thearrangement of the outlet orifices of the nozzle provides a narrowplume. In yet a further aspect, the outlet orifices are arranged so thatthe initial path of the compound as it exits the nozzle is substantiallyparallel to the central axis of the nozzle. In yet another aspect, theoutlet orifices are arranged in parallel alignment, in a line of equaldistance from a center of the nozzle, in an arrangement that providesfor the delivery of a narrow plume, in an arrangement that provides aninitial path of the compound as it exits the nozzle substantiallyparallel to the central axis, or combinations thereof.

In an embodiment, the angle of the plume delivered from the nozzle isabout 5 degrees, about 4 degrees, about 3 degrees, about 2 degrees,about 1 degree, inclusive of endpoints. In an embodiment, the angle ofthe plume delivered from the nozzle is about 5 degrees. In yet anotherembodiment, the angle of the plume is 5 degrees, is 4 degrees, is 3degrees, is 2 degrees, or is 1 degree. In a further embodiment, theangle of the plume delivered from the nozzle is 5 degrees.

In embodiments of the nozzle, the impact force delivered by the nozzlehaving more than one outlet orifice is decreased.

In embodiments of the nozzle, the delivery time is decreased fordelivery of a compound by a nozzle having more than one outlet orifice.

In another embodiment of the nozzle, the delivery time and the impactforce is decreased by a nozzle having more than one outlet orifice.

In embodiments of the nozzle, the outlet orifices are arranged so thatthe propellant entrains the compound to be delivered. Without beingbound by theory with regards to entrainment of the compound, themultiple streams exiting the nozzle created by the plurality of outletorifices are better able to entrain air within the plume, therebyshielding the edges of the plume against friction induced turbulence atthe edges of the plume.

As shown in FIG. 1, a drug product inlet 2 is configured to receive amixture of gas propellant and a drug formulation. The drug formulation(prior to mixing with the gas propellant) may be in the form of apowder, dispersion, liquid or other suitable nasal delivery dosage form.A nozzle body 4 is secured to the drug product inlet 2. The mixture ofgas propellant and drug formulation pass through circular, tube-shapednozzle channels 6 before exiting the outlet orifices 8, 12 thusreleasing the mixture. The circular, tube-shaped nozzle channels 6aligned parallel to a longitudinal axis running through the center ofthe nozzle body 4. The distal surface 10 of the nozzle body 4 is shownin the distal view along with the outlet orifices 12.

In one embodiment, the drug product inlet may be optional. In anotherembodiment, the nozzle has an attachment mechanism to the source of thecompound being distributed from the nozzle. The attachment mechanism maybe a screw, snap or other suitable mechanism. In another embodiment, thedrug product inlet and nozzle may be of uniform construction with thechamber, container or the like holding the compound being delivered.When the drug product inlet is optional, a proximal end of the nozzlefunctions as the drug product inlet.

The channels may be circular, oval, square, triangular, parallelograms,trapezoidal or combinations thereof.

In one embodiment, the nozzle shown in FIG. 1 is described in Example 6.

As shown in FIG. 2, a drug product inlet 14 is configured to receive amixture of gas propellant and a drug formulation. A nozzle body 16 issecured to the drug product inlet 14. The mixture of gas propellant anddrug formulation pass through circular, tube-shaped nozzle channels 18before exiting the outlet orifices 20 thus releasing the mixture. Thecircular, tube-shaped nozzle channels 18 being tapered away from alongitudinal axis running through the center of the nozzle body 16.

As shown in FIG. 3, a drug product inlet 22 is configured to receive amixture of gas propellant and a drug formulation. A nozzle body 24 issecured to the drug product inlet 22. The mixture of gas propellant anddrug formulation pass through circular, tube-shaped nozzle channels 26before exiting the outlet orifices 28. The circular, tube-shaped nozzlechannels 26 being tapered toward a longitudinal axis running through thecenter of the nozzle body 24.

As shown in FIG. 4, a drug product inlet 30 is configured to receive amixture of gas propellant and drug formulation. A nozzle body 32 issecured to the drug product inlet 30. The mixture of gas propellant anddrug formulation pass through conically-shaped channels 34 beforeexiting the outlet orifices 36 thus releasing the mixture. Theconically-shaped channels 34 are aligned to taper away from alongitudinal axis running through the center of the nozzle body 32. Theoutlet orifices 36 (at the distal end of the channels 34) being largerin diameter than the proximal end of the channels 34.

As shown in FIG. 5, a drug product inlet 38 is configured to receive amixture of gas propellant and drug formulation. A nozzle body 40 issecured to the drug product inlet 38. The mixture of gas propellant anddrug formulation pass through conically-shaped channels 42 beforeexiting the outlet orifices 44 thus releasing the mixture. An axis alongthe center of the conically-shaped channels 42 being parallel to alongitudinal axis running through the center of the nozzle body 40. Theoutlet orifices 44 (at the distal end of the channels 42) being smallerin diameter than the channels 42 at the proximal end of the channels 42.

Shown in FIG. 6 are five (5) circular outlet orifices 48 disposed at thedistal end of a nozzle body 46 in a pentagonal orientation. Shown inFIG. 7 are six (6) circular outlet orifices 52 disposed at the distalend of a nozzle body 50 in a hexagonal orientation. Shown in FIG. 8 aresix (6) circular outlet orifices 56 disposed at the distal end of anozzle body 54 in a centered-pentagonal orientation. Shown in FIG. 9 arefour (4) circular outlet orifices 60 disposed at the distal end of anozzle body 58 in a linear orientation. Shown in FIG. 10 are four (4)rectangular outlet orifices 64 disposed at the distal end of a nozzlebody 62 in a radial orientation. Shown in FIG. 11 are five (5)star-shaped outlet orifices 68 disposed at the distal end of a nozzlebody 66 in a pentagonal orientation. As shown in FIGS. 6-11, the volumebetween outlet orifices 48, 52, 56, 60, 64, 68 is solid. In anotherembodiment, the volumes may be void, partially void or partially solid.

In one embodiment, the outlet orifices are square, circular, oval,trapezoidal, parallelograms, triangular, star shaped, or combinationsthereof.

In one embodiment, the nozzle shown in FIG. 6 is described in Example 1.

In another embodiment, the nozzle shown in FIG. 9 is described inExample 3.

Shown in FIG. 12 are five (5) circular outlet orifices 74 disposed atthe distal end of the nozzle body 70 in a pentagonal orientation. Inthis embodiment, the volume 72 between the channels is void (e.g., anair gap).

In one embodiment, the nozzle shown in FIG. 12 is described in Example2.

As shown in FIG. 13, a drug product inlet 76 is configured to receive amixture of gas propellant and a drug formulation. A nozzle body 78 issecured to the drug product inlet 76. The mixture of gas propellant anddrug formulation pass through circular, tube-shaped nozzle channels 80before exiting the outlet orifices 82 thus releasing the mixture. Inthis embodiment the outlet orifices channels 80 extend beyond the nozzlebody 78 and terminate at the outlet orifices 82 which are biased withthe biased edge oriented near to and parallel to a longitudinal axisrunning through the center of the nozzle body 78. Nozzle #35B, as shownin FIG. 18, has outlet orifice channels which extend beyond the nozzlebody.

In one embodiment, the nozzle shown in FIG. 13 is described in Example4.

As shown in FIG. 14, a drug product inlet 84 is configured to receive amixture of gas propellant and a drug formulation. A nozzle body 88 issecured to the drug product inlet 84. The mixture of gas propellant anddrug formulation pass through circular, tube-shaped nozzle channels 90before exiting the outlet orifices 92 thus releasing the mixture. Inthis embodiment there is a rounded inlet guide 86 attached to the nozzlebody 88 and pointed into the drug product inlet 84 which directs thedrug product into the nozzle channels 90. There also exists an outletdirectional guide which guides the drug product coming out of the outletorifices 92 to help maintain a narrow drug product spray. The nozzle isnozzle 31 shown in FIG. 19.

In one embodiment, the nozzle shown in FIG. 19 is described in Example5.

As shown in FIGS. 27 and 28, a bypass nozzle is shown and described.Nozzle C (Example 11) describes an annular gas bypass nozzle. Nozzle Cincludes a chamber for the compound to be delivered and a chamber forthe propellant. In one aspect, the compound is a drug and the propellantis a gas. The drug may be in liquid or powder form. Nozzle C includes achannel to transport the drug. This drug channel is centered inside ofanother channel, the propellant channel, which serves to deliver thepropellant. In one aspect, the drug channel transports a powder whilethe propellant channel delivers a gas. The dimensions of the drugchannel with respect to the propellant channel affects the amount andvelocity of gas emitted from the outlet of the nozzle. Both the powdertransport channel and the gas channel can be altered to change theperformance of the nozzle assembly, as discussed in Example 11.

Upon actuation of nozzle C, both chambers are pressurized and gas isemitted from the end of the nozzle as a uniform and symmetrical hollowcylinder, while at the same time the dose is emitted into the center ofthe gas cylinder. Depending on the configuration of the two channels andthe amount and type of gas used to drive the nozzle, the relativevelocity of the gas and powder streams can be different, causingdifferent effects on performance. In one embodiment, multiple dosetransport channels are placed in the center of the gas transport tube sothat this nozzle design would deliver doses of more than one drug at thesame time with minimal mixing before the drugs are deposited on thetarget surface or tissue.

In one embodiment, the drug channel can transport a liquid, a powder, agas, or combinations thereof.

In one embodiment, a bypass nozzle D is shown as in FIG. 28. Nozzle Dshows a check shut off valve. The valve includes a ball of plasticslightly smaller than the diameter of the compound chamber behind thenozzle. Upon activation of the device, the ball rolls up behind the drugand seats on the back side of nozzle D, thereby effectively preventinggas flow through the drug channel once the drug is released.

A variety of compounds may be delivered by the nozzle. In oneembodiment, a mixture of drug and gas propellant is delivered by thenozzle. In another embodiment, a mixture of liquid propellant and drugis delivered by the nozzle. In another embodiment, a liquid propellantis delivered by the nozzle. In yet another embodiment, a drug isdelivered by the nozzle. In yet other embodiments, a combination ofcompounds is delivered by the nozzle.

The compound delivered by the nozzle may be a liquid, gas, solid, orcombinations thereof. The compound may be a liquid or a powder. Thecompound may be a drug.

The nozzle may be used to deliver compounds to many environments. Thenozzle may be used to deliver a compound intranasally. The nozzle may beused to deliver a compound orally, rectally, vaginally, topically, tothe eye, or intranasally.

The nozzle may be used to deliver medicaments or other compounds not fortherapeutic use. For example, the nozzle may be used to deliver aprecise plume in manufacturing.

EXAMPLES

Set forth below are examples of nozzles and outlet orifices.

Example 1

In nozzle number 1, a five outlet nozzle was constructed of 30 gauge (G)stainless steel tubes, (approximately 0.0069 inch circular orifice andapproximately 5 mm in length) mounted within a 20 G stainless steeltube. The 30 G tubes fit tightly and formed a symmetric pentagonalarrangement that would lie symmetrically on a circle. All non-orificegaps between the individual 30 G tubes were filled. The distal end ofthe nozzle was finished with all tubes flush and of equal length. Theopenings were finished clean and square.

Example 2

Nozzle number 2 was constructed having 11 outlets composed of 5, 25 Gstainless tubes (approximately 0.011 inch circular orifice andapproximately 5 mm in length) mounted within an 18 G stainless steeltube for a tight fit. No voids between the 25 G and 15 G tubes werefilled, so the nozzle configuration had 5 additional ports,approximately triangular in shape, the nozzle ports surrounding the 5circular ports. In addition, a central void of roughly pentagonal shapeexists at the very center which was capable of passing a dose. Thedistal end of the nozzle was finished with all tubes flush and of equallength. The openings were finished clean and square.

Nozzle number 3, as shown in FIG. 22, was constructed having 6 outletscomposed of 3, 23 G stainless tubes assembled into a 15 G stainlesssteel tube. These fit tightly and no glue or filler was used. Inaddition to the three nozzle ports from the 23 G tubes, there were threeadditional approximately triangular shaped outlets from the nozzle. Thedistal end of the nozzle was finished with all tubes flush and of equallength. The openings were finished clean and square.

Nozzle number 10 has some of the same components used to assemble nozzlenumber 3. For nozzle number 10, each 23 G stainless tube has anapproximately 30 degree bend in the last 2 mm of the tube at the distalend of the nozzle. These tubes were inserted into a 14 G stainless steeltube so that their orientation was all the same around the perimeter ofthe 14 G tube. These were held in place with a central brass rod. Thedistal end of the nozzle was finished with all tubes flush and of equallength. The openings were finished clean and square. Because of the 30degree bend in the 23 G tubes, they are oval in dimensions and notround. All voids between elements were open.

Nozzle number 11 has some of the same components of nozzle number 9(Example 3) with straight 23 G stainless steel tubes set into a 14 Gstainless steel tube. No brass rod was used to hold the tubes in, withthe 14 G tube being lightly crimped. The distal end of the nozzle wasfinished with all tubes flush and of equal length. The openings werefinished clean and square. All voids between elements were open.

Nozzle number 13 has some of the same components as nozzle number 2.Similar to nozzle number 1 (Example 1), nozzle number 13 has allintervening open voids filled leaving 5 active nozzle ports in the samespecial relationship as those in nozzle number 2.

Example 3

Nozzle number 5 has four outlets of 30 G stainless steel tubes in alinear arrangement within a modified 16 G stainless steel tube. The 30 Gtubes were set by light crimping of the 16 G tube and filler was appliedto fill all voids between the 30 G and 16 G tubes. The distal end of thenozzle was finished with all tubes flush and of equal length. Theopenings were finished clean and square.

Example 4

Nozzle number 12 has five outlets consisting of 27 G stainless steelneedle ends arranged with the pointed ends extending beyond the end ofthe nozzle housing (a 16 G stainless steel tube). All five 27 G needleswere arranged so that the point was placed closest to the center of theassembly. The assembly of 5 needles was secured within the 16 G tubeunder tension from a centrally placed brass rod. The brass rod wastapered so that a tension fit held everything together. All voids otherthan the 5 outlet ports were filled with epoxy prior to final assembly.The resulting nozzle had a tapered distal end that extendedapproximately 2.66 mm from the end of the 16 G nozzle housing. All portsurfaces were finished clean and square.

Nozzle 19 is a composite assembly of nozzle number 37 (Example 6) with27 G stainless steel needles inserted into the port channels of a nozzlenumber 37 nozzle assembly. The needles extend from the plastic end ofthe distal end of the nozzle by approximately 5.5 mm. The needles areall arranged so that the tip side of each needle is oriented toward thecenter of the nozzle. They lie closest to the central axis of thenozzle.

Example 5

Nozzle number 14 has seven outlet ports arranged around a centralaerodynamic extension, analogous to nozzle number 7 (Example 8 and FIG.24). Nozzle number 14 was cast in plastic rather than assembled withstainless steel tubing. The central extension is 2.15 mm in diameter atthe point that it joins the distal end of the nozzle and tapers in anaerodynamic fashion. The port channels are straight and parallel to thenozzle axis. The port channels are 5.5 mm long. The nozzle assemblyincludes a female luer lock.

Nozzle number 15 is similar to nozzle number 14 but with the body of thesection of the assembly before the nozzle proper being shorter whilestill including a female luer lock. Nozzle number 15 is cast entirely inplastic as a unit.

Example 6

Nozzle number 16 has 4 outlet ports arranged approximately 0.7 mm apartand equidistant in a square pattern. Nozzle number 16 has a similarfemale luer lock design as for nozzle number 15 (Example 5). Port lumenlengths are approximately 5.3 mm in length, parallel to each other andon axis with the nozzle body. Cast entirely in plastic as a unit.

Nozzle number 37 is similar to nozzle number 16, except 5 outlet portsarranged equidistant to each other and as if placed on a circle or theapices of a pentagon. Port channel lengths are 5.3 mm and include thesame luer lock as nozzle number 16. Cast entirely in plastic as a unit.

Nozzle number 38 has 4 outlet ports as in nozzle number 16. The portchannels of nozzle number 38 traverse 10.3 mm and they possess a righthanded twist (as viewed at the distal end) of approximately 180 degreesin that distance. The nozzle is longer than nozzle 16 and contains thesame luer features and spatial details as nozzle 16. Cast entirely inplastic as a unit.

Example 7

Nozzle number 4, as shown in FIG. 23, was constructed having 7 outletscomposed of 3, 25 G stainless tubes (approximately 21 mm in length)assembled into a 15 G stainless tube. The 15 G tube was lightly crimpedon its perimeter to secure the 25 G tubes within the body. No adhesivewas used and all voids remained open. The distal end of the nozzle wasfinished with all tubes flush and of equal length. The openings werefinished clean and square.

Example 8

Nozzle number 7, as shown in FIG. 24, was constructed of 14, 30 Gstainless steel tubes arranged within a 14 G stainless tube around acentral steel aerodynamically sculpted pin. The 30 G tubes are 14 mm inlength and are seated flush with the end of the 14 G nozzle housing. Thecentral pin is approximately 1.12 mm in diameter. It protrudes from thedistal end of the nozzle by 2.38 mm. No glue is used to set theseelements within the 14 G tube. All perimeter voids participate in themovement of liquid and gas through the nozzle. Except for the extendedcentral pin, the distal end of the nozzle was finished with all tubesflush and of equal length. The openings were finished clean and square.

Example 9

Nozzle number 8, as shown in FIG. 25, has similarities to nozzle number7 described in Example 8 without the use of 30 G tubes on the periphery.Thin rectangular brass standoffs were used to center the central pinwithin the 14 G stainless steel tube. Eight standoffs were required tocenter and maintain the pin in a linear orientation with respect to the14 G tube.

Example 10

Nozzle number 9, as shown in FIG. 26, is constructed of 14, 30 Gstainless steel needle tips with similarities to the 30 G tubes ofnozzle number 7. These tubes are mounted around the same type of centralsteel aerodynamically sculpted pin. Each tapered needle tip is mountedwith the long side placed against the steel pin. The result is a 3 mmtapered extension at the distal end beyond the edge of the 14 G nozzlehousing.

Example 11

Nozzles for the delivery of a dry powdered dose.

The nozzles of this Example are shown in FIGS. 27 and 28.

Nozzle A. Single port nozzle. Several configurations of solid plasticdrilled with a straight exit port of varying lengths were tested. A 4.45mm diameter plastic nozzle with a single 1.07 mm internal diameter portof approximately 1 cm in length was tested. Also tested was a 4.45 mm indiameter nozzle with a single 0.67 mm internal diameter port of 8.75 mmin length. A third configuration was a nozzle of approximately 1 cm inlength with a single nozzle port of 0.031 inch internal diameter. Thepowder is driven through the port tube by gas pressure.

Nozzle B. Multiple port nozzle. Drilled in PEEK plastic. 5 nozzle portsof internal diameter of 0.015 inch. Orifice diameters are 0.011 inches.The dose is driven through the multiple ports by gas pressure.

Nozzle C. Single port annular gas bypass nozzle. Two configurations weredesigned and tested. This nozzle design is a two compartment nozzle, onefor the dose and one for gas. These nozzles feature a straight 0.031 ininternal diameter port tube that transports the powder. This transporttube is centered inside of another tube that serves to deliver a streamof gas. The configurations tested have different gas tube diameters andtherefore affect the amount and velocity of gas emitted from the end ofthe nozzle. Both the powder transport tube and the gas tubes can bealtered to change the performance of the nozzle assembly. These testconfigurations were designed to be driven by a single source ofcompressed gas (e.g. hydrofluoroalkane), but each compartment of thenozzle could be independently driven. Upon actuation, both chambers arepressurized and gas is emitted from the end of the nozzle as a uniformand symmetrical hollow cylinder, while at the same time the dose isemitted into the center of the gas cylinder. Depending on theconfiguration of the two tubes and the amount and type of gas used todrive the nozzle, the relative velocity of the gas and powder streamscan be different, causing different effects on performance.

The inner diameter of the dose tube is 0.031 in for all three nozzles.The zero (0) bypass nozzle is the third configuration described in Aabove. Low bypass nozzle has a gas tube gap of 0.008 in. The high bypassnozzle has a gas tube gap of 0.016 in.

Nozzle D. A variant of nozzle C was made and tested, shown in FIG. 28.It is possible that excess propellant gas emitted from the dose tubeafter the dose chamber is emptied of powder can cause interference withthe plume. In that event, a check shutoff valve was conceived andtested. The valve consisted of a ball of plastic slightly smaller thanthe diameter of the dose chamber behind the nozzle. Upon activation ofthe device, the ball rolls up behind the dose and then seats on the backside of the nozzle, thereby effectively preventing gas flow through thedose tube once the dose is gone.

Example 12

Analytical Methods Employed for Nozzle Testing

Plume Geometry

Plume angle was tested as a performance criterion. The testing of thenozzles included establishing the angle of the plume and/or the size ofthe deposition area at a fixed distance from the nozzle tip.

1) Photography. The pattern of expelled high pressure water from thenozzle was photographed and the angle described by the pattern on theprinted photo was measured. This method proved to be accurate andreproducible. Additional methods would look at describing the plumeangle of an aerosolized plume as would be generated during actual use.Photography data was used as comparison data for the nozzles describedherein.

2) Blotter paper deposition. A method was developed that relied on thedeposition of a stained (Fluorescein) aqueous dose emitted from a nozzleonto a blotter paper held at a distance of 4 cm. 4 cm was chosen as adistance relevant to the distance needed to traverse from a likelynozzle tip position in the human naris to the upper olfactory region ofthe human nasal sinus. This blotter paper deposition assay offered theadvantage of creating a permanent record of the dose deposition. Inaddition, it would be capable of showing any asymmetry in plumegeometry. Plume angles were calculated using the blotter paperdeposition. A limitation of this method is that the dose staining canbleed beyond the region of deposition, thereby making the observeddeposition spot to be larger than the actual deposition zone. This isespecially true for larger dose volumes and for nozzles that concentratethe dose into the smallest zone. Another limitation is that the methoddescribes the end result of the deposition and cannot describe howdeposition occurs over the course of the event. This limitation yieldsless information about the nature of the plume as it starts, progressesand ends. It can say very little about how the plume is affected by itstravels through the air from nozzle to target.

Two additional approaches designed to analyze plume geometry during thetime course of dose delivery were applied.

3) High speed blotter recording, with dose deposition onto a rapidlyspinning blotter paper target. This method is able to create a physicalrecord of deposition over time. The blotter disk can be rotated fastenough so that dose spread is reduced and appears to yield accurateplume geometries displayed during the full shot. It appears to be ableto discriminate between different nozzle designs and can catchasymmetries in plume geometry.

4) The second method is high speed videography (greater than 200 framesper second) enhanced with fluorescent dye and lighting. This methodappears capable of discriminating the performance between differentnozzle designs and can record defects in performance. This method hasbeen adapted for studying nozzle performance under various situations,such as free air performance and within human nasal models.

5) An adaptation of method high speed videography. Modified lightingconditions were used to enhance the visualization of powder doses. Insome cases lighting was adjusted so that only limited sections of thespray plume were visible. White light illumination is valuable forseeing the overall plume geometry for powder, however white light iseasily scattered and is not able to report on the various dose densitieswithin a plume and likely best highlights the surface of a powder plume.Using single wavelength light in the red spectrum is able to reducelight scatter and better penetrate a powder plume.

Dose Deposition

Previous methods are principally directed at understanding plumegeometry generated by each nozzle. We used these methods to attaincertain pre-determined performance parameters, such as symmetrical andnarrow plumes, to predict actual performance in use. An in vitro methodfor assessing nozzle performance was to measure dose depositionefficiency in human nasal models. We have employed several methods forthis, differing mostly in the manner in which we quantitate the amountof dose deposited in different areas of the human nasal sinus. Of thethree methods developed, here we report data generated from two methods.

5) One method assessed deposition by dose weight and was able to reportonly dose weight deposited in our upper olfactory region of interest(ROI) and elsewhere.

6) Another method reports dose deposition through optical densitometry.This method is capable of reporting fractional deposition within ourupper olfactory ROI as well as any number of other ROI that are userdefined.

Impact Force

Another physical performance characteristic that affected nozzle designwas the impact force generated by the developed plume from any nozzle.We developed a method that records impact force profiles (includingmaximal impact force) for the duration of a dose shot. Forces generatedduring dosing could be compared to other commercially available nasalspray devices.

Results:

Plume Geometry:

Many of the nozzles described herein have principle deposition zonedimensions of 3 mm or less when fired 4 cm from the target withrelatively minor amounts of dose outside of 5 mm. This represents aplume angle of about 5 degrees or under. It should be noted that thedimensions of the upper olfactory region of the human nasal sinus is onthe order of several mm eventually narrowing down to 1-2 mm.

An early deposition study (method 5) along with a study with method 3allowed a direct comparison between some of the nozzles described inthis application with a nozzle designed to generate a rotating plume andalso to a single port device (urethral tip).

TABLE 1 % Olfactory Deposition - Method 5 Deposition 5 5 degrees Zone 1010 degrees away Nozzle Dimensions - Direct degrees degrees toward fromName Method #3 aim posterior anterior septum septum Rotational 25-30 mm2.8 4.2 9.9 1.23 2.4 Plume Prototype #1B 25 mm 19 12.5 20.9 22 16 #2 13mm 58.3 30.2 49.1 45.6 54.8 #13 8 mm 59.4 45.7 55.9 63.2 57.3 #1 * 66 6667.4 64.3 65 Urethral ** 56.5 28.7 39.5 35.8 52.3 Tip * Not doneconcurrently with the other nozzles under the same conditions, however,later comparisons between #1 and #13 reveal that #1 has a smallerdeposit footprint than #13. ** Not done

As shown in Table 1, high speed blotter paper deposition analysis wascarried out with each nozzle in this experiment with the exceptions ofnozzle number 1 and the urethral tip. Later comparisons with nozzlenumber 1 revealed that nozzle number 1 is able to achieve the smallestdeposition zone for any of the nozzles tested. The urethral tip is alsoable to achieve a deposition zone approaching that of nozzle number 13.

The deposition study presented in Table 1 shows the average from atleast three nozzle firings for each nozzle and each aim angle. Allconditions of firing were the same for all the nozzles and for eachfiring condition studied. A correlation can be made between the size ofthe dose deposition zone and the percent of dose deposited in the upperolfactory region of a human nasal model. The correlation persistsregardless of the aim angle used for these shots. We conclude that thesmaller the dose plume angle is, the higher the deposition in our ROI.Not expected from these results is that some of the nozzles appear toperform better regardless of the aim of the nozzle. In contrast, theurethral tip, which has a single nozzle port and generates a single plumstream, appears to be more sensitive to aim angle. While the urethraltip has good deposition (though by no means the best) when aimeddirectly at the target, its performance falls off dramatically at mostother angles. We generally see with this data that multiport nozzles,which generate multiple stream plumes, perform better in off-anglescompared to the single port nozzle.

The experimental results presented in the FIG. 29 demonstrate howparallel multistream plumes appear to be more resistant to plumedegradation over greater distances. All nozzles can be seen to havenarrow deposition zones. The single port nozzles #20 and #21 appear todegrade faster upon distance from the nozzle tip. This can especially beseen with nozzle #21. The smallest diameter single port nozzle hascomparability to the multi-dose nozzles, but the constraint of thisnarrow port (⅕th the port area of the 0.0069 in 5 port nozzle) adverselyaffects the time of full dose delivery and/or the forces generated bythe plume on potentially sensitive nasal membranes (see Table 2 below).

Two measured parameters, nasal model deposition and plume stability,point to a parallel multistream nozzle configuration being better ableto maintain a narrow dose plume while traveling to the target. Ourresults demonstrate a narrow plume can deposit on the narrow recessedupper olfactory region of the human nasal sinus. Also, a multistreamdose plume appears to better negotiate the intricacies of the complexhuman sinus. The off-angle performance advantage for a multistream doseplume compared to the urethral catheter (e.g., a single port 0.020 inchnozzle) demonstrates that clearly. Without being bound by theory, it maybe that the ability of a multistream dose plume's ability to entrain air(essentially forming an air capsule) is capable of solving both of thesechallenges (nasal model deposition and plume stability). Such an aircapsule may reduce peripheral turbulent degradation of the dose steam aswell as buffer its interaction with the walls of the nasal sinus.

Table 2 addresses the property of shot duration for various narrow plumenozzles. Multi port nozzles have the advantage of initiating andcompleting dose delivery in relatively short times. In contrast, thebest performing single port nozzle (with respect to deposition zone)required in excess of 50 milliseconds to complete a reduced volume dose.The single port nozzles would greatly limit the size of the dose that adevice could deliver. A 50 μL dose would take in excess of 100milliseconds and a 100 μL dose nearly 2/10ths of a second. This is toolong for a user actuated device. Even if increasing the single portaperture to 0.020 in, which could in theory bring the shot durationperformance into line with the multiport nozzles, performance is lost,as shown in Tables 1 & FIG. 29. Alternatively, increased pressure mightbe able to reduce the shot time for nozzle #20, but the impact forcefrom such a stream is more likely to be damaging to sensitive tissues.

TABLE 2 Nozzle Description - Spray Deposition - Method 3 - High SpeedDisk Number of Ports & Spray Deposition Fine Mist* Width Spray doseSpray duration Nozzle Name Port Diameter (inch) zone width @ 4 cm @ 4 cmvolume** in μL Milliseconds #1 5 ports @ 0.0069 1.95 mm 10.26 mm 30 28.4#13 5 ports @ 0.0110 2.39 mm  8.19 mm 40 4.6 #22 5 ports @ 0.0060 2.18mm  9.73 mm 40 19.1 #23 5 ports @ 0.0110 2.87 mm 11.15 mm 40 3.1 #20 1port @ 0.0070 1.36 mm 9.09 25 56.0 *Each spray deposition results insome small fraction of the dose that is deposited at some distance fromthe central dense deposition zone. This is measurable with this methodand is likely less than 10% of the dose. **The maximal dose load was 40μL for this experiment. However, for those nozzles with restricted flow,less volume was required in order to measure the greatly extendedduration of the spray.

Table 2 shows physical dimensions of spray plume and duration of sprayfor 4 parallel multiport nozzles and one single port nozzle.

Example 13

Powder Nozzles

FIG. 30 shows the effect that a bypass nozzle can make on a plume ofpowder as it is ejected out of a nozzle into free air. In most cases asimple tubular powder nozzle will display what is shown in FIG. 30. Thefront of the plume appears to form a bullet point shape. Video analysisshows that likely mechanism causing this is that the powder is ejectedfrom the nozzle as a ballistic stream and the leading edge isimmediately met by resistance from the air that it is moving into. Thisappears to be met by additional material fed into the back of thisturbulent feature. In cases where the nozzle has clogged mid shot, the“bullet” plume essentially comes to a rest. The propagation of the plumethrough the ambient air requires additional force from the freshmaterial emanating from the nozzle.

In contrast, the bypass nozzles do not possess this feature. The powderappears to be buffered against impact with any stationary air in thefiring path. Without being bound by theory, we believe that thepropellant that exits the nozzle has displaced the stationary air,replacing it with a forward moving stream of gas. This forward stream ofgas likely paves the way or carries the powder as if on a slipstreammoving in the direction aimed. Additional studies have shown whatappears to be more tightly collimated powder streams when fired from thebypass nozzles, as shown in FIG. 30.

FIG. 31 demonstrates again how the high bypass generated slipstreamappears to negate the leading edge bullet point and turbulence that asimple zero bypass nozzle generates. In this case where the plumes aredirected between two plates 1.8 mm apart also shows how the powderstreams generated by the high bypass nozzle can remain collimated ascompared to that caused by the zero bypass nozzles.

Example 14

Nozzle 18 was constructed of qty. five (5) metal tubes with an internaldiameter of 0.01 inches and an external diameter of 0.02 inchescontained within a 15 metal tube with an internal diameter of 0.054inches and an external diameter of 0.070 inches. The metal tubes arefrictionally secured. Air gaps are disposed between the needles. Nozzle18 is illustrated in FIGS. 12 and 17.

Nozzle 35 b included five (5) outlet orifices with a diameter of 0.008inches which extend out from the housing body and terminate as sharppoints. Nozzle 35 b is illustrated in FIGS. 7, 13, and 18.

Nozzle 31 included qty. seven (7) outlet orifices with diameter of 0.015inches. Nozzle 31 is illustrated in FIGS. 14 and 19.

Nozzle 33 included qty. five (5) outlet orifices each with a diameter of0.015 inches. The outlet orifices on the distal end of Nozzle 33 areillustrated in FIGS. 6 and 20.

Nozzle 17 was constructed with five outlet orifices with a diameter of0.006 inches. The outlet orifices on the distal end of Nozzle 17 areillustrated in FIGS. 6 and 21.

Set forth in Table 3 is data generated using various nozzles inaccordance with the invention.

TABLE 3 Average deposition % @ 0 deg horizontal and Outlet OrificeAverage Impact Force Nozzle vertical Diameter (in) (grams) 29   62%0.054 4.00 ± 0.22 18 58.3 0.054 4.06 ± 0.86 35B 45.7% 0.0075 2.04 ± 0.5931 33.9% 0.015 2.42 ± 0.37 33 41.6% 0.015 2.32 ± 0.57 17 66.0% 0.0071.99 ± 0.08

Average deposition was done with the nozzle aimed at optimal orientationinto a human nasal sinus model. Depositions were determined by doseweights deposited onto model surfaces with the average of a minimum ofthree experiments.

Spray plume diameter and Average impact force measurements were takenwith nozzles positioned at 4 cm distant from recording device. Outletorifice diameter is by direct measurement.

The invention claimed is:
 1. A method for delivering a compound to anupper olfactory region of a nasal cavity, the method comprising:actuating a nozzle positioned for intranasal delivery of the compound toa subject, wherein actuating the nozzle pressurizes a proximal end ofthe nozzle, the nozzle including a propellant chamber housing apropellant and a compound chamber housing the compound and including acheck shut off valve, a body of the nozzle defining a compound channeland a propellant channel, the compound channel being disposed within thepropellant channel; transporting the compound from the compound chamberand through the compound channel, the compound channel having a proximalend and a distal end, the proximal end being configured to receive thecompound, the distal end of the compound channel having an outletorifice exiting to the nasal cavity; transporting a propellant from thepropellant chamber and through the propellant channel, the propellantchannel having a proximal end and a distal end, the proximal end beingconfigured to receive the propellant, the distal end of the propellantchannel having an outlet orifice exiting to the nasal cavity, and thepropellant channel fluidly isolated from the compound channel;preventing, by the check shut off valve, propellant from flowing throughthe compound channel once the compound is released from the compoundchamber; and releasing the compound from the outlet orifice of thecompound channel and the propellant from the outlet orifice of thepropellant channel directly into the nasal cavity, wherein once exited arespective outlet orifice, the compound and the propellant form a plumehaving a width of 5 degrees or less to enable the plume to reach theupper olfactory region of a nasal cavity.
 2. The method of claim 1,wherein the nozzle further includes at least a second compound channel,wherein the nozzle is capable of delivering more than one compound at atime.
 3. The method of claim 1, wherein the compound is a liquid, apowder, a gas, or combinations thereof.
 4. The method of claim 1,wherein the check shut off valve comprises a ball having a diametersmaller than a diameter of the compound chamber, and wherein the ball ismade of plastic.
 5. The method of claim 4, wherein preventing thepropellant from flowing through the compound channel comprises causingthe ball to roll to the distal end of the compound channel to a locationbehind an opening of the nozzle thereby preventing the propellant fromflowing through the compound channel.
 6. The method of claim 1, whereinthe compound channel is centered within the propellant channel.
 7. Amethod for delivering a compound to an upper olfactory region of a nasalcavity, the method comprising: actuating a nozzle positioned forintranasal delivery of the compound to a subject, wherein actuating thenozzle pressurizes a proximal end of the nozzle, the nozzle including apropellant chamber housing a propellant and a compound chamber housingthe compound, a body of the nozzle defining a compound channel and apropellant channel, the compound channel being disposed within thepropellant channel; transporting the compound from the compound chamberand through the compound channel, the compound channel having a proximalend and a distal end, the proximal end being configured to receive thecompound from the compound chamber, the distal end of the compoundchannel having an outlet orifice exiting to the nasal cavity;transporting a propellant from the propellant chamber and through thepropellant channel, the propellant channel having a proximal end and adistal end, the proximal end being configured to receive the propellantfrom the propellant chamber, the distal end of the propellant channelhaving an outlet orifice exiting to the nasal cavity, and the propellantchannel fluidly isolated from the compound channel; preventingpropellant from flowing through the compound channel once the compoundis released from the compound chamber; and releasing the compound fromthe outlet orifice of the compound channel and the propellant from theoutlet orifice of the propellant channel directly into the nasal cavity,wherein once exited a respective outlet orifice, the compound and thepropellant form a plume having a width of 5 degrees or less to enablethe plume to reach the upper olfactory region of a nasal cavity.
 8. Themethod of claim 7, wherein the nozzle further includes at least a secondcompound channel, wherein the nozzle is capable of delivering more thanone compound at a time.
 9. The method of claim 7, wherein the compoundis a liquid, a powder, a gas, or combinations thereof.
 10. The method ofclaim 7, wherein preventing propellant from flowing through the compoundchannel comprises preventing by a check shut off valve, the check shutoff valve comprising a ball having a diameter smaller than a diameter ofthe compound chamber, wherein the ball is made of plastic.
 11. Themethod of claim 10, wherein preventing propellant from flowing throughthe compound channel comprises causing the ball to roll to the distalend of the compound channel to a location behind an opening of thenozzle thereby preventing the propellant from flowing through thecompound channel.
 12. The method nozzle of claim 7, wherein the compoundchannel is centered within the propellant channel.